Abstract: The recent World Health Organization policy statement on pneumococcal conjugate vaccines (PCVs) endorsed a schedule of 3 primary doses without a booster (3p+0 schedule) or, as a new alternative, 2 primary doses with a booster dose (2p+1 schedule) considering the cost for low- income countries. PCV13 was licensed in the U.S. for 3 primary doses plus a booster (3p+1 schedule) supported by high efficacy demonstrated by 2 large scales US-based clinical trials. A clear understanding of the full impact of reduced-dose schedules of PCV on protective antibody levels and functionality as well as induction of immunologic B- and T- cell memory is lacking. This study will determine specific immune responses of children receiving 2 primary doses, 3 primary doses and 3p+1 doses of PCV13 and provide for the first time direct comparison of IgG antibody levels, functional antibody differences and cellular immune memory differences in the same cohort of children. Clinically relevant significant differences in levels of antibodies, functional antibodies, and memory B-cell and CD4+ T-cell responses can be measured after 2 compared to 3 primary doses of PCV13 and a booster dose in the second year of life that stimulates clinically relevant increases in antibodies, memory B-cell and CD4+ T-cell responses. We will explore this hypothesis by comparing immune responses in prospectively collected blood samples from infants after 2p vs. 3p doses of PCV13 and pre vs. post booster PCV13. Prospectively collected blood samples of children at 4 time points after PCV13 doses will be analyzed to quantitate differences in immune responses. Healthy children aged 6-18 months from Rochester, NY, USA will have samples of plasma and immune cells studied after PCV13 doses. The study will provide a novel assessment of antibody levels and functionality as well as B- and T-cell memory immune responses against all PCV13 serotypes following 2p vs. 3p doses and pre vs. post booster doses in children. Remarkably few studies have looked at the antibody responses against all 13 polysaccharides in one cohort of children and none have simultaneously focused on examination of B- and T-cell specific memory. The findings will strengthen or bring to question policy decisions impacting children worldwide regarding recommendations for PCV administration schedules. Understanding the impact of each dose of PCV13 to generate replenished memory B-cell pool and T helper cells will provide valuable information to assess any changes in immunization schedules.